Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa.

Abstract

Mutations involving elastic tissue proteins result in a broad spectrum of phenotypes affecting skin, skeleton, ocular and vascular structures, including tortuous blood vessels and cutis laxa. Here we report on a female newborn with apparently long fingers, aortic aneurysm, tortuous pulmonary arteries and mild generalized lax skin. She died at 27 days of age due to severe respiratory distress and inoperable systemic vascular abnormalities. Skin biopsy showed marked paucity and fragmentation of elastic fibers and autopsy revealed occlusion of the pulmonary artery. DNA analysis identified compound heterozygous mutations ((c.835C > T (p.R279C)/c.1070_1073dupCCGC) in fibulin-4, a recently recognized elastic fiber associated protein. Analyses of dermal fibroblasts from the patient indicated that fibulin-4 mRNAs with the 4-bp duplication transcribed from one allele are probably subject to nonsense-mediated decay, whereas synthesis and secretion of the missense R279C fibulin-4 protein from the other allele is severely impaired. Immunostaining demonstrated a total absence of fibulin-4 fibers in the extracellular matrix deposited by the patient's fibroblasts. Our studies provide evidence that deficiency in fibulin-4 leads to a perinatal lethal condition associated with elastic tissue abnormalities.

• Authors: Majed Dasouki, Dessislava Markova, Robert Garola, Takako Sasaki, Noe L Charbonneau, Lynn Y Sakai, Mon-Li Chu
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 143A Issue 22 Pg. 2635-41 (Nov 15 2007) ISSN: 1552-4825 [Print] United States
• PMID: 17937443 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• EFEMP2 protein, human
• Extracellular Matrix Proteins

Topics

• Abnormalities, Multiple
• Aortic Aneurysm (etiology, genetics)
• Arachnodactyly (etiology, genetics)
• Arterial Occlusive Diseases (etiology, genetics)
• Cutis Laxa (etiology, genetics)
• Elastic Tissue (pathology)
• Extracellular Matrix Proteins (deficiency, genetics)
• Fatal Outcome
• Female
• Heterozygote
• Humans
• Infant, Newborn
• Mutation
• Pulmonary Artery